Clinical Utility of Semistructured Interview and Scales to Assess Withdrawal Syndromes With Dose Reduction or Discontinuation of Selective Serotonin Reuptake Inhibitors or Serotonin Norepinephrine Reuptake Inhibitors

Abstract Background Withdrawal syndromes can occur after dose reduction or discontinuation of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Few measurement instruments are available to assess them: Diagnostic Clinical Interview for Drug Withdrawal 1–New Symptoms of SSRI and SNRI (DID-W1) and Discontinuation Emergent Signs and Symptoms (DESS) checklist. We assessed their interrater reliability, verified the percent agreement between the two, and tested DESS sensitivity and specificity on the basis of the diagnoses formulated via the DID-W1. Methods One-hundred thirty-four subjects who referred for withdrawal at 3 outpatient facilities were enrolled and assessed via the DESS and the DID-W1. Percent agreement and Cohen κ were calculated to measure DID-W1 and DESS interrater reliability, as well as the agreement between DID-W1 and DESS items. Sensitivity and specificity of DESS were derived from the identification of true-positive, false-negative, true-negative, and false-positive on the DID-W1. Results Both tools showed excellent interrater reliability (DID-W1 Cohen κ = 0.958; DESS Cohen κ = 0.81–1). The degree of agreement between DID-W1 and DESS items was poor or fair (Cohen κ < 0.40) for some items and moderate (Cohen κ = 0.41–0.60) for others. Sensitivity and specificity of DESS were 0.937 (true-positive = 60, false-negative = 4) and 0.285 (true-negative = 20, false-positive = 50), respectively. Conclusions DID-W1 was a reliable method to identify and diagnose withdrawal syndromes. The DESS checklist showed to be a useful tool for detecting withdrawal SSRI/SNRI symptoms when the aim is to achieve high sensitivity to identify true positives.

W ithdrawal is commonly seen with antidepressant use and has been reported in more than half (56%) of patients with discontinuation. 1 In the first systematic review on selective serotonin reuptake inhibitors (SSRIs), Fava et al 2 found up to 40% of patients experienced new-onset symptoms with abrupt discontinuation or gradual tapering of SSRIs. Fava et al 3 also published the first systematic review on serotonin-norepinephrine reuptake inhibitors (SNRIs) showing that withdrawal symptoms occur after their abrupt discontinuation or gradual tapering. 3 These reviews posited the need for a new classification of withdrawal symptoms 2,3 to detect the range of symptoms experienced by patients and diagnose withdrawal syndromes specific to SSRI/SNRI. 4 Based on classical concepts of central nervous system drug withdrawal, Chouinard and Chouinard 5 proposed specific diagnostic criteria to identify 3 withdrawal syndromes, which can occur with decrease or discontinuation of SSRI/SNRI. These diagnostic criteria for SSRI/SNRI were elaborated from well-established withdrawal categories for central nervous system drugs. They include (1) new withdrawal symptoms, which are new to the patient and not part of the original psychiatric illness, as previously reported with benzodiazepines 6 ; (2) rebound symptoms, which consist in a rapid return of the patient's original psychiatric illness at a greater intensity than before treatment; both first and second categories are transient, reversible, characterized by a peak of onset within 36 to 96 hours after discontinuation or dose reduction of SSRIs/SNRIs, and usually last up to 6 weeks 6 ; and (3) persistent postwithdrawal disorders, which may consist of new withdrawal symptoms or rebound (preexisting) symptoms, but are long-lasting, severe, potentially irreversible, persisting more than 6 weeks and characterized by a peak of onset between 24 hours and 6 weeks. [7][8][9] Recently, Cosci et al 10 developed a semistructured diagnostic interview, the Diagnostic Clinical Interview for Drug Withdrawal 1-New Symptoms of SSRI and SNRI (DID-W1), to diagnose withdrawal syndromes at dose reduction or discontinuation of SSRI/ SNRI according to Chouinard and Chouinard 5 diagnostic criteria. In a pilot study, the DID-W1 interview showed excellent interrater agreement, 10 allowing for the diagnosis of withdrawal syndromes. Another widely used tool to assess signs and symptoms associated with SSRI discontinuation is the Discontinuation Emergent Signs and Symptoms (DESS). 11 It can be administered as a self-rated dimensional instrument or as a clinician-rated checklist. It attempts to parse out new symptoms, versus old symptoms, and whether the old symptoms are worse, unchanged, or improved. The tool has no diagnosis purposes and cannot be used to assess persistent postwithdrawal symptoms, which have been clearly identified years later the creation of the DESS and whose prevalence estimate is still in need of being measured.
The aim of the present study was to assess interrater reliability of the DID-W1 and the DESS, to verify the percent agreement between DID-W1 and DESS items, and to test DESS sensitivity and specificity using the DID-W1 as a diagnostic tool. There is need of differentiating withdrawal symptoms from syndromes and confront criteria with dimensional assessments.

Participants
Participants were consecutively recruited at 3 third-level psychiatric outpatients' facilities (the Pharmachopsychology Service at the University of Florence, the Outpatient Resistant Depression Unit of Institute of Psychiatry at the Federal University of Rio de Janeiro, and the Kurume University Hospital) from July 2018 to December 2020 among patients for whom withdrawal symptomatology was suspected.
The following inclusion criteria were applied: (1) age 18 years or older; (2) history of SSRI/SNRI decrease/discontinuation; and (3) referring at least 1 symptom that occurred immediately after decrease or discontinuation of an SSRI or an SNRI. Exclusion criteria were (1) dose decrease/discontinuation of more than 1 SSRI/SNRI or decrease/discontinuation of SSRI/SNRI concurrent with dose decrease/discontinuation of other psychotropic medications, because their effects could overlap, and (2) intellectual disability.
Subjects were independently assessed by 2 raters per center using both the DID-W1 10 and the DESS. 11 Raters (ie, trained clinical psychologists or psychiatrists) had clinical experience and followed a join practical training with guidance of the authors of the interview and data collection for a previous pilot study. 10 The raters did not communicate during the testing session or afterward regarding the assessment and the scoring. The filled DID-W1 and DESS were stored in sealed envelopes, which were opened at the time of statistical analysis. Sociodemographic and clinical data were collected as previously described. 12 The study was approved by the Ethic Committee of the University Hospital Careggi (Florence, Italy), and participants provided written informed consent.

Instruments
The DID-W1 10 is a brief semistructured clinical interview that allows for the diagnosis of withdrawal syndromes with decrease or discontinuation of SSRI/SNRI according to Chouinard and Chouinard 5 diagnostic criteria. The interview has 5 modules, previously described 10 : the DID-W1-Personal Data, collecting sociodemographic and clinical information (which allow also to discriminate between discontinuation-related symptoms and symptoms that are part of the original mental illness); the DID-W1-Screening Questions, screening on lifetime use of SSRI/SNRI; the DID-W1-Withdrawal Symptoms 1 (WS1), informing the diagnosis of current (section a) or lifetime (section b) new withdrawal symptoms; the DID-W1-Withdrawal Symptoms 2 (WS2), informing the diagnosis of current (section a) or lifetime (section b) rebound withdrawal symptoms; and the DID-W1-Withdrawal Symptoms 3 (WS3), informing the diagnosis of current (section a) or lifetime (section b) persistent postwithdrawal disorders. Items are rated with a dichotomous response format (yes/no). The administration of the interview requires on average 30 minutes. For the present study, the administration of the interview required a median of 35.5 minutes (minimum, 20 minute; maximum, 60 minutes).
In a preliminary study conducted in 17 subjects, the DID-W1 showed an excellent interrater agreement (% of agreement: 97.06%; Cohen κ = 0.85 with 95% confidence interval [CI] of 0.61-1.08; squared correlation coefficient = 0.72). 10 The DESS 11 is an instrument that queries for signs and symptoms associated with discontinuation of treatments inhibiting serotonin reuptake. A total score can be calculated, but subjects are considered at risk of experiencing a withdrawal syndrome if the number of DESS events increases by 4 or more during the discontinuation period. The instrument has 43 items and can be administered in a clinician-rated form (as in the present research), in a self-rated form, or as an interactive voice-response form. For the present research, subjects were asked whether they have experienced changes in symptoms since the last decrease or discontinuation of SSRI/SNRI and were invited to identify each symptom as new, old (but worse), old (but improved), old (but unchanged), or not present. 13,14 Each item is scored 0/1.

Statistical Analysis
Interrater reliability was tested via the percent agreement, Cohen κ, 15 and 95% CI. Because κ cannot be directly interpreted, a squared correlation coefficient, named coefficient of determination, was used. 16 The percent agreement was also used to verify the agreement between DID-W1-WS1a and DESS items. The following matching between DID-W1-WS1a and DESS items was applied: irritability   To calculate DESS sensitivity and specificity, 18 subjects were split in 4 groups: true-positive (TP: ill and test positive); falsepositive (FP: not ill but test positive); false-negative (FN: ill but test negative); and true-negative (TN: not ill and test negative) 19 based on the assessment run via the DID-W1. Sensitivity (SN) was calculated as the proportion of TPs correctly identified: SN = TP/(TP + FN). Specificity (SP) was calculated as the proportion of TNs correctly identified: SP = TN/(TN + FP). 19,20 Because, according to the DESS instructions, a change of 4 symptoms is needed to suspect a withdrawal syndrome, 11 the rate of subjects who met a diagnosis of DID-W1 "current new withdrawal symptoms" was calculated among those who had at least 4 DESS "new symptoms" to test specificity and sensitivity of DESS regarding this diagnosis. Similarly, the rate of subjects who met a diagnosis of DID-W1 "current rebound withdrawal symptoms" was calculated among those who presented at least 4 DESS "old symptoms but worse" and, the rate of subjects who met the diagnosis of DID-W1 "current persistent postwithdrawal disorders" was calculated among those who presented at least 4 symptoms among DESS "new symptoms" and "old symptoms but worse." The statistical analyses were performed using IBM SPSS Statistics version 21. A P ≤ 0.05 was considered statistically significant.

Clinical Characteristics
Among the 150 subjects invited to participate, 134 took part in the research, 14 declined to participate-not being interested, and 2 did adhere for time reasons. Mean age ± SD was 39.63 ± 10.17 years, 59.7% (n = 80) were females. Approximately 29% (n = 39) had a high school education or higher, 40.3% (n = 54) were employed, and 47% (n = 63) were married. For the majority of subjects (83.6%; n = 112), the episode of possible withdrawal assessed for the present research was related to SSRI decrease/discontinuation. For 22 subjects (16.4%), the episode of possible withdrawal assessed was related to SNRI decrease/ discontinuation.

Percent Agreement Between DID-W1-WS1a and DESS
Items with a slight or poor strength of agreement were as follows: anxiety, depression, anger or aggression, agitation, cognitive symptoms, dysphoria, sleep disturbances, headache. Irritability general symptoms, neuromuscular symptoms, and nausea showed a fair strength of agreement. Decreased concentration, tremor, dizziness or lightheaded, gastrointestinal symptoms, and sensory symptoms had a moderate strength of agreement (Table 3).

DISCUSSION
The DID-W1 showed excellent interrater reliability (percent agreement of 97%), which is consistent with the preliminary study. 10 The DESS checklist also showed excellent interrater reliability.
The degree of agreement between DID-W1-WS1a and DESS differed according to items. A poor strength of agreement was found for psychological symptoms (ie, anxiety, depression, anger or aggression, agitation, cognitive symptoms, dysphoria, sleep disturbance), whereas a moderate strength of agreement (Cohen κ value = 0.41-0.60) was found for physical symptoms (ie, tremor, dizziness or lightheaded, gastrointestinal symptoms, sensory symptoms). It can be hypothesized that a checklist, such as the DESS, may more readily identify physical symptoms, whereas psychological symptoms may be more fully captured using tailored questions in a semistructured interview, such as the DID-W1.
DESS sensitivity and specificity were inversely proportional as expected 21 and suggested that the DESS should be preferred to identify TPs, thus as a screening tool. However, when the 3 withdrawal syndromes were considered, sensitivity was low, and specificity was high for current new withdrawal symptoms and current rebound withdrawal symptoms, and vice versa for current persistent One limitation is the relatively small sample size, which does not allow for higher rates of current new withdrawal symptoms and current rebound withdrawal symptoms diagnoses and also introduces a limitation related to the questioned independence of the sensitivity/specificity and prevalence. Many empirical studies suggested that the disease prevalence may impact sensitivity and specificity. However, this sample of 134 subjects is unique in the literature on this topic, which has been largely explored via Web reports. Another limitation is that individuals were retrospectively assessed. Future prospective studies are warranted. The population under observation is a strength of the study. In addition, this is the first research examining interrater reliability of DESS and DID-W1, strength of agreement between their items, DESS sensitivity, and specificity. 22 The present study has possible implications. The first area of application of DESS and DID-W1 is in naturalistic studies aimed at identifying prevalence of withdrawal syndromes; such prevalence is still unknown in the literature. Longitudinal studies may also benefit from the use of these instruments to clarify the relationships between withdrawal syndromes and other manifestations of drug-induced behavioral changes (eg, refractoriness, loss of effects). 23 The second area has to do with the differentiation between relapse and withdrawal in trials aimed at testing for both short-term effects and long-term, preventive, or prophylactic effects of psychotropic medications. [24][25][26] The various effects of discontinuing treatment with psychotropic medications can compromise the scientific soundness of research, especially in trials, which involve discontinuing a previous or current active treatment to a placebo. They are in need of distinguishing between early withdrawal-associated reactions (eg, new withdrawal symptoms and rebound), late withdrawal-associated reactions (eg, persistent postwithdrawal disorders), and later, posttreatment discontinuation reemergence of psychiatric illness. The third area of potential application is the identification of treatment resistance depression, discriminating it from tolerance phenomena within the heterogeneous components of the category. 27 In addition, being the DESS is a good screening tool for current persistent postwithdrawal disorders, it might be routinely used by psychiatrists and clinical psychologists for the assessment of patients undergoing SSRI/SNRI discontinuation; the fact that the DESS is generally proposed as a self-rating scale reinforces its use as a screening method. In case the DESS suggests a possible withdrawal syndrome, and if the clinician can devote approximately 30 minutes to further assess the patient, a more refined clinimetric diagnosis 28 might be reached via the DID-W1. Particularly persistent postwithdrawal disorders might need a more accurate assessment representing a major clinical problem. Differently from new withdrawal and rebound symptoms (which are de facto acute withdrawal), they are long lasting, severe, and reduce the working, social, and family functioning of the patients. 29 In addition, the use of the DIDW-1 might help clinicians in differentiating between withdrawal and relapse. This is another vexing clinical dilemma with serious implications because a diagnostic mistake may drive clinicians to inadequately reintroduce the SSRI/SNRI. In practice, having assessed the patients via the DID-W1 and a diagnostic interview for DSM (Diagnostic and Statistical Manual of Mental Disorders) psychiatric disorders, clinicians may use the DID-W1 diagnoses as exclusion criteria for DSM diagnoses similarly to what they do for medical conditions. The overall priority, thus, would be to formulate an accurate diagnosis, which is the condition sine qua non for an appropriate treatment and for prevention. 29 Further, the use of DESS as a screening tool and DID-W1 as a diagnostic tool follows the principles of incremental validity, which refers to the unique contribution or incremental increase in predictive power associated with the inclusion of a particular assessment procedure in the clinical decision process. 30 Although the DESS is focused on current symptoms, the DID-W1 explores both current and lifetime clinical phenomena and provides a chronological appraisal of symptoms as well as a longitudinal development of disorders. 31 In brief, the present research suggests that the DID-W1 is a reliable tool to diagnose withdrawal syndromes after dose decrease or discontinuation of SSRI/SNRI according to Chouinard and Chouinard 5 criteria, and the DESS is an adequate screening tool for withdrawal syndromes, especially persistent postwithdrawal disorders. Because these instruments are available, and their properties are known, we recommend using them in clinical and research settings to refine the use and indications of antidepressants, including differences in drug-induced behavioral changes among antidepressants. 4